The objective of this R01 proposal, from an interdisciplinary team of researchers at Duke University, North Carolina State University and the University of Michigan, is to develop a label-free optical nanobiosensor that measures biomolecular interactions in real-time for the detection of category A pathogens. This objective is motivated by the urgent need for low-cost, portable and high-throughput sensors that can detect pathogens that pose significant danger to our society either through biological warfare or terrorist activities. The nanobiosensor is based upon nanoparticle surface plasmon resonance (nanoSPR), in which the collective oscillations of electrons in noble metal nanoparticles and core-shell structures, is induced by visible light. The proposed project couples fundamental research in nanostructured material properties, nanoparticle synthesis, and biomolecular interactions into a coherent program with significant biomedical impact, because it will lead to the development of a generic nanotechnology platform for the label-free, real-time detection of protein-ligand interactions. The greatest impact of this proposal for homeland defense against bioterrorism will be the development of readily manufacturable, low-cost, easy-to-use, disposable nanobiosensors for detection of category A pathogens and their protein markers for point-of-care (poc) clinical diagnostics and environmental monitoring. The technology also transcends biodefense with potential application to other infectious agents where cost-effect, portable, and time-efficient detection is also important. The attractive features of the nanoSPR sensor are: (1) that it will enable real-time, label-free detection of biomolecular interactions so that no additional reagents are required to detect the analyte of interest; (2) it can be implemented in an array format for rapid, high-throughput screening of a panel of pathogens; and (3) the nanoSPR biosensor will be fabricated by two different technologically simple and scaleable methodologies that will enable large-volume and low-cost manufacturing of the nanoSPR chips.